It has been known that JAK3, as well as JAK1, JAK2 and TYK2, is a non-receptor tyrosine kinase belonging to a JAK family, and that JAK3 is involved in the signaling of various cytokines.
JAK1, JAK2 and TYK2 are expressed in a wide range of tissues, whereas the expression of JAK3 is mainly limited to lymphocytes such as T cells, B cells, and natural killer cells. JAK1- and JAK2-deficient mice are embryonic lethal, or die soon after they are born. On the other hand, JAK3-deficient mice or humans develop severe combined immunodeficiency due to the dysfunction of lymphocytes.
It is assumed that a JAK3 inhibitor will inhibit the signals of six types of cytokines (i.e., IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21), so as to specifically suppress the function of lymphocytes such as T cells or B cells, which play an important role in an immune system. Thus, such a JAK3 inhibitor is expected to be an effective therapeutic agent for diseases associated with activation of the aforementioned cells, having minimum expression of side effects (Non Patent Documents 1 and 2).
It has been reported that examples of the disease, which can be treated with the JAK3 inhibitor, include autoimmune disease (rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, scleroderma, polymyositis-dermatomyositis, Sjogren's syndrome, Behcet's disease, etc.), allergic disease (bronchial asthma, allergic rhinitis/hay fever, atopic dermatitis, food allergy, anaphylaxis, drug allergy, hives, conjunctivitis, etc.), nervous system disease (multiple sclerosis, Alzheimer's disease, etc.), inflammatory bowel disease (ulcerative colitis, Crohn's disease), psoriasis, contact dermatitis, diabetes, celiac disease, viral infectious disease, acute respiratory distress syndrome (ARDS), graft-versus-host disease (GVHD), transplant rejection, hematologic malignancy (lymphoma, leukemia), and other malignant tumors (Non Patent Documents 3 to 6).
Clinically, Tofacitinib (Pfizer), which is a JAK3 inhibitor, has been used as a therapeutic agent for rheumatoid arthritis. However, it has been reported that Tofacitinib has low selectivity to JAK3, and thus that this agent has side effects (lipid increase, anemia, neutropenia, immunosuppression, etc.), which are caused by the inhibition of JAK1 and JAK2 by the agent (Non Patent Document 7).
Moreover, it has been reported so far that a pyrrolopyrimidine compound having a cyclic substituent at position 4 (Patent Document 1), a pyrrolopyrimidine compound having cyclohexene at position 4 (Patent Document 2), and a pyrrolopyrimidine compound having an aromatic group substituted with acrylamide at position 4 (Patent Document 3) exhibit JAK-inhibiting activity.